|Year : 2021 | Volume
| Issue : 1 | Page : 52-55
Need for abundant caution in prophylactic application of chloroquine and hydroxychloroquine for viral infections including COVID-19: Possibility of increased susceptibility
Samsung Health Division, Samsung Research Institute, Noida, Uttar Pradesh, India
|Date of Submission||09-Apr-2020|
|Date of Acceptance||13-Jan-2021|
|Date of Web Publication||29-Jun-2021|
Samsung Health Division, Samsung Research Institute, Noida, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Significant interest in the application of chloroquine (CQ) and hydroxychloroquine (HCQ) for prophylaxis and treatment of COVID-19 has been recently reported throughout the world. In the light of this, it has become important to revisit the mechanisms of action, as well as clinical evidence for the efficacy of CQ and HCQ in similar viral infections. We note that while some evidence exists for therapeutic efficacy of CQ and HCQ in mitigating morbidities associated with virus-induced inflammation and immunohyperactivity, abundant caution is necessary for expecting prophylactic efficacy in the light of therapeutic evidence. In particular, we intend to draw urgent attention to the fact that the same immunosuppresive and immunomodulatory properties of CQ and HCQ which render them useful as therapeutic agents in viral pneumonia and cytokine storm syndrome are also expected to make them dangerous prophylactic agents against viral infections. We also intend to draw attention to some other potential concerns associated with widespread prophylactic usage of CQ and HCQ.
Keywords: Chloroquine, COVID-19, hydroxychloroquine, prophylaxis, severe acute respiratory syndrome coronavirus 2
|How to cite this article:|
Singh R. Need for abundant caution in prophylactic application of chloroquine and hydroxychloroquine for viral infections including COVID-19: Possibility of increased susceptibility. J Mahatma Gandhi Inst Med Sci 2021;26:52-5
|How to cite this URL:|
Singh R. Need for abundant caution in prophylactic application of chloroquine and hydroxychloroquine for viral infections including COVID-19: Possibility of increased susceptibility. J Mahatma Gandhi Inst Med Sci [serial online] 2021 [cited 2021 Jul 24];26:52-5. Available from: https://www.jmgims.co.in/text.asp?2021/26/1/52/319840
In vitro anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential of chloroquine (CQ) and hydroxychloroquine (HCQ) has been recently reported.,, Observations from more than 100 patients in China have shown the potential efficacy of CQ in dealing with COVID-19-associated pneumonia. In an open-label nonrandomized clinical trial with 26 COVID-19 patients conducted in France, a combination of HCQ and azithromycin has also been shown to have potential efficacy in decreasing the SARS-CoV-2 viral load.
HCQ is being investigated for prophylaxis and treatment of COVID-19 in several clinical trials in the United States. A multicountry mega clinical trial named SOLIDARITY is underway led by the World Health Organization (WHO) to test the effects of CQ and HCQ, among other antiviral drug combinations, in clinical outcomes of COVID-19. The National Taskforce for COVID-19 of the Indian Council of Medical Research (ICMR) has even recommended the use of HCQ for prophylaxis of SARS-CoV-2 for high-risk population, namely asymptomatic health-care workers involved in care of COVID-19 patients, as well as household caregivers of COVID-19 patients. CQ and HCQ are being evaluated as potential mitigating agents in COVID-19-induced pneumonia in 23 clinical trials in China.
The WHO has acknowledged that CQ has received significant attention as a prophylactic and curative agent for COVID-19 throughout the world, so much so that widespread shortages are being reported and even more are expected, primarily due to prophylactic consumption and storage.
With this unprecedented interest in prophylactic intake of CQ and HCQ, it has become important to revisit the body of evidence with regard to efficacy, mechanisms of action, and clinical outcomes of CQ and HCQ in dealing with viral infections.
| Concern 1: Increased Risk of all Infections (Including COVID-19) from Chloroquine/Hydroxychloroquine-Mediated Immunosuppression and Immunomodulation|| |
This is the biggest concern by far: quite against widely held hope and expectation, prophylactic intake of CQ and HCQ may increase susceptibility to SARS-CoV-2, as well as other pathogens.
It is well established that CQ and HCQ have a significant immunosuppressive effect,,,,,,,,,, as well as immunomodulatory effect., This has made them very successful in long-term management of immunomediated conditions such as rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, graft-versus-host diseases, and to some extent, even carcinogenic tumors.,,,,,,
Indeed, it is this immunosuppressive and immunomodulatory effect that is responsible for at least a portion of positive clinical outcomes associated with therapeutic use of CQ and HCQ in viral infections,, including in COVID-19.
It has become well known that for almost all severe viral infections, a portion of morbidity can be attributed to inflammation, immunohyperactivity, and in severe cases, a cytokine storm syndrome.
A cytokine storm is a possible sacrificial macro-apoptosis, whereby an immune system, when unable to control an infection, triggers a cytokine-mediated chain reaction initiating a widespread attack on healthy tissues. This can lead to organ failure and even death, if uncontrolled. Although the reason behind such a peculiar suicidal response is unclear, one possible explanation could be that this is a mechanism to prevent further spread of infection in the population.
A cytokine storm-related morbidity is commonly observed in advanced cases of most viral respiratory diseases including influenza, H5N1 flu, H1N1 flu, SARS, and other coronaviruses.,, Similar inflammatory immunohyperactivity has been observed in severe cases of COVID-19, and has also been proposed as a primary cause of mortality.
Thus, CQ and HCQ are expected to be therapeutically effective for COVID-19-induced pneumonia, which has also been observed in preliminary clinical trials in China.
However, for the same reason, prophylactic ingestion of CQ and HCQ can reduce immunopotency and increase susceptibility to the entire spectrum of viral, bacterial, and other infections. This could be especially dangerous if such a prophylactic regime of CQ or HCQ is administered to high-risk health workers and caregivers of COVID-19 patients, which has been recommended by the ICMR.
The main aim of this article is to call urgent attention to this: prophylactic efficacy is, at best, unrelated to, and independent of therapeutic efficacy. In other words, there is no reason to believe that a drug with a positive therapeutic potential is also expected to have a positive prophylactic potential only by the virtue of its therapeutic potency. In the case of CQ and HCQ with regard to viral infections, therapeutic and prophylactic efficacy may even be inversely correlated.
Therapeutic intervention in infectious diseases involves intervention in pathogen survival, pathogenic action, pathogen replication, or alleviation of severe symptoms, whereas prophylactic intervention in infectious diseases involves reducing the likelihood of infection, increasing the likelihood of immunomitigation, or reducing pathogen replication.
Only a drug impairing pathogenic replication, which has low toxicity and minimal side effects, can play a role both in therapeutic and prophylactic interventions. For example, CQ and HCQ themselves impair the Plasmodium replication lifecycle by preferential accumulation in the acidic food vacuoles of Plasmodium trophozoites in erythrocytes. This increases the vacuole pH, disrupting hemoglobin proteolysis, and resulting in toxicity due to free heme. Since they affect pathogen replication, CQ and HCQ are useful as both therapeutic and prophylactic interventions for malarial infections.
However, there is no evidence for any effect of CQ and HCQ in SARS-CoV-2 replication or any other action in vivo. In vitro reduction in SARS-CoV-2 endosomes due to CQ and HCQ has been observed,,, probably because of increase in pH of endosomes and lysosomes. However, the primary pathogenic activity of SARS-CoV-2 does not happen by infection via endocytosis through the endosome–lysosome pathway. Instead, it is well understood that SARS-CoV-2 carries out its pathogenic activity using its spike protein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor proteins on some human cell membranes.
Moreover, this inhibitory effect of CQ and HCQ toward viral endosomes is not expected to be specific to SARS-CoV-2. This is because, the mechanism of action in this case is only related to the formation of endosomes through endocytosis and their merger with lysosomes and not to the kind of virus encapsulated in the endosome. Indeed, similar inhibitory effects of CQ and HCQ have been observed in vitro for other viruse.,,, However, similar positive effects have not been replicated in vivo, and even negative clinical and diagnostic outcomes were observed in the case of some viral infections,,,,, as well as other infections.
The chikungunya virus (CHIKV) is a noteworthy case in point. While CQ and HCQ have been shown to be effective both prophylactically and therapeutically in vitro against CHIKV,, in vivo therapeutic trials have shown increased arthralgia morbidities with no viremial benefit. Even exacerbation of acute CHIKV infection with increased viremia and slower viral clearance was observed in CQ and HCQ prophylactic trials in vivo,, possibly due to their immunosuppressive effects.
| Concern 2: Increased Malarial Resistance to Chloroquine and Hydroxychloroquine|| |
CQ and HCQ have traditionally played a critical prophylactic role in preventing malarial infections throughout the world. However, in recent times, Plasmodium strains have shown increasing resistance to CQ and HCQ, thus greatly reducing their effectiveness.
Widespread and unmanaged use of CQ and HCQ as a prophylactic agent for COVID-19 will further enhance resistance in the Plasmodium population leading to an even greater reduction in the effectiveness of CQ and HCQ as a prophylactic and therapeutic intervention for malarial infections.
| Concern 3: Unavailability of Chloroquine and Hydroxychloroquine for other Critical Therapies|| |
As noted earlier, CQ and HCQ have shown effectiveness in therapeutical mitigation of diseases with an inflammatory etiology including rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, graft-versus-host diseases, and viral cytokine storms.,,,,, CQ and HCQ have also shown some positive effects against carcinogenic tumors,, apart from traditional effectiveness against malaria.
Widespread demand for CQ and HCQ as prophylactic agents for COVID-19 has resulted in significant shortages and reduced availability for other such critical diseases. These shortages are expected to increase if the demand for CQ and HCQ remains unmanaged.
| Concern 4: Side Effects of Chloroquine and Hydroxychloroquine|| |
A complete study of the side effects of CQ and HCQ is outside the scope of this article. However, it must be remembered that while relatively less toxic, CQ and HCQ are not free from side effects and toxicity at high dosage.,,
The half-life of CQ in the human body is 30 h, which is relatively long and difficult to mitigate in case of an adverse reactionary response. CQ overdose has been associated with life-threatening cardiovascular disorders, psychiatric complications, and even mortality. Unfavorable side effects in the skin, eyes, and brain have been recorded in cases with long term usage of CQ.
These side effects and toxicity must be kept in mind while considering CQ and HCQ for large-scale intake as prophylaxis against COVID-19.
| Conclusion|| |
Abundant caution needs to be exercised in recommending and using CQ and HCQ as prophylactic agents for COVID-19, especially in the light of their well-recorded immunosuppressive and immunomodulatory properties.
CQ and HCQ have been repeatedly verified to be ineffective against viral infection and replication in vivo. Even more critically, increased susceptibility to a wide range of infections has been observed on prophylactic and therapeutic administration of CQ and HCQ for viral infections.
We do not intend to persuade against therapeutic application of CQ and HCQ for their anti-inflammatory properties to mitigate SARS-CoV-2-induced pneumonia and inflammatory immunohyperactivity. We mainly intend to caution against expecting prophylactic efficacy on account of therapeutic evidence or evidence from malarial prophylaxis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al
. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro
. Cell Discov 2020;6:16.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al
. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro
. Cell Res 2020;30:269-71.
Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res 2020;177:104762.
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020;14:72-3.
Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al
. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;56:105949.
Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care 2020;57:279-83.
Hackstein H, Thomson A. Dendritic cells: Emerging pharmacological targets of immunosuppressive drugs. Nature Rev Immunol 2004;4:24-35.
Pascolo S. Time to use a dose of chloroquine as an adjuvant to anti-cancer chemotherapies. Eur J Pharmacol 2016;771:139-44.
Kazama I, Maruyama Y, Murata Y, Sano M. Voltage-dependent biphasic effects of chloroquine on delayed rectifier K+-channel currents in murine thymocytes. J Physiol Sci 2012;62:267-74.
Hunzelmann N, Moinzadeh P, Genth E, Krieg T, Lehmacher W, Melchers I, et al
. High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy. Arthritis Res Ther 2009;11:R30.
Salmeron G, Lipsky PE. Immunosuppressive potential of antimalarials. Am J Med 1983;75:19-24.
Nishimura M, Hidaka N, Akaza T, Tadokoro K, Juji T. Immunosuppressive effects of chloroquine: Potential effectiveness for treatment of post-transfusion graft-versus-host disease. Transfus Med 1998;8:209-14.
Norris DA, Weston WL, Sams WM. The effect of immunosuppressive and anti-inflammatory drugs on monocyte function in vitro
. J Lab Clin Med 1977;90:569-80.
Oravisto KJ, Alfthan OS. Treatment of interstitial cystitis with immunosuppression and chloroquine derivatives. Eur Eurol 1976;2:82-4.
Panayi GS, Neill WA, Duthie JJ, McCormick JN. Action of chloroquine phosphate in rheumatoid arthritis. 1. Immunosuppressive effect. Ann Rheum Dis 1973;32:316-8.
Chauhan A, Tikoo A. The enigma of the clandestine association between chloroquine and HIV-1 infection. HIV Med 2015;16:585-90.
D'Alessandro S, Scaccabarozzi D, Signorini L, Perego F, Ilboudo DP, Ferrante P, et al
. The use of antimalarial drugs against viral infection. Microorganisms 2020;8:85.
Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012;76:16-32.
Gao R, Bhatnagar J, Blau DM, Greer P, Rollin DC, Denison AM, et al
. Cytokine and chemokine profiles in lung tissues from fatal cases of 2009 pandemic influenza A (H1N1): Role of the host immune response in pathogenesis. Am J Pathol 2013;183:1258-68.
Channappanavar R, Perlman S. Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017;39:529-39.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al.
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al
. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-8.
Khan M, Santhosh SR, Tiwari M, Lakshmana Rao PV, Parida M. Assessment of in vitro
prophylactic and therapeutic efficacy of chloroquine against Chikungunya virus in vero cells. J Med Virol 2010;82:817-24.
Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: What to expect for COVID-19? Int J Antimicrob Agents 2020;55:105938.
Lamballerie XD, Boisson V, Reynier JC, Enault S, Charrel RN, Flahault A, et al
. On chikungunya acute infection and chloroquine treatment. Vector Borne Zoonotic Dis 2008;8:837-9.
Roques P, Thiberville SD, Dupuis-Maguiraga L, Lum FM, Labadie K, Martinon F, et al
. Paradoxical effect of chloroquine treatment in enhancing chikungunya virus infection. Viruses 2018;10:268.
Maheshwari RK, Srikantan V, Bhartiya D. Chloroquine enhances replication of Semliki forest virus
and encephalomyocarditis virus in mice. J Virol 1991;65:992-5.
Bönsch C, Kempf C, Mueller I, Manning L, Laman M, Davis TM, et al
. Chloroquine and its derivatives exacerbate B19V-associated anemia by promoting viral replication. PLoS Negl Trop Dis 2010;4:e669.
Seth P, Mani H, Singh AK, Banaudha KK, Madhavan S, Sidhu GS, Gaddipati JP, et al
. Acceleration of viral replication and up-regulation of cytokine levels by antimalarials: Implications in malaria-endemic areas. Am J Trop Med Hyg 1999;61:180-6.
Qin X, Chen G, Fen Y, Zhu X, Du Y, Pang W, et al
. Early treatment with chloroquine inhibits the immune response against Plasmodium yoelii
infection in mice. Tohoku J Exp Med 2014;234:271-80.
Bijker EM, Bastiaens GJ, Teirlinck AC, van Gemert GJ, Graumans W, van de Vegte-Bolmer M, et al
. Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity. Proc Natl Acad Sci U S A 2013;110:7862-7.
Sutherland CJ, Haustein T, Gadalla N, Armstrong M, Doherty JF, Chiodini PL. Chloroquine-resistant Plasmodium falciparum
infections among UK travellers returning with malaria after chloroquine prophylaxis. J Antimicrob Chemother2007;59:1197-9.